Nature Chose Phosphates and Chemists Should Too: How Emerging P(V) Methods Can Augment Existing Strategies.

Kyle W Knouse,Julien C Vantourout,Michael A Schmidt,Ivar M Mcdonald,Dillon T Flood,Phil S Baran,Martin D Eastgate

doi:10.1021/acscentsci.1c00487

Abstract

Phosphate linkages govern life as we know it. Their unique properties provide the foundation for many natural systems from cell biology and biosynthesis to the backbone of nucleic acids. Phosphates are ideal natural moieties; existing as ionized species in a stable P(V)-oxidation state, they are endowed with high stability but exhibit enzymatically unlockable potential. Despite intense interest in phosphorus catalysis and condensation chemistry, organic chemistry has not fully embraced the potential of P(V) reagents. To be sure, within the world of chemical oligonucleotide synthesis, modern approaches utilize P(III) reagent systems to create phosphate linkages and their analogs. In this Outlook, we present recent studies from our laboratories suggesting that numerous exciting opportunities for P(V) chemistry exist at the nexus of organic synthesis and biochemistry. Applications to the synthesis of stereopure antisense oligonucleotides, cyclic dinucleotides, methylphosphonates, and phosphines are reviewed as well as chemoselective modification to peptides, proteins, and nucleic acids. Finally, an outlook into what may be possible in the future with P(V) chemistry is previewed, suggesting these examples represent just the tip of the iceberg.

Highlights

INTRODUCTION AND HISTORICAL PERSPECTIVEThe study of phosphate has led to a deep understanding of the chemistry that makes life on Earth possible
It is clear that phosphates and phosphate esters underpin almost all biological function including genetic information storage, energy storage, compartmentalization, lipid bilayers, and signaling phosphates and phosphate esters underpin almost all biological function including genetic information storage, energy storage, compartmentalization, lipid bilayers, and signaling
The elementary enzymatic steps of terpene and steroid biosynthesis involve the assembly-line-like construction of polyunsaturated systems from a simple building block: dimethylallylpyrophosphate (DMAPP).[8]

Summary

■ INTRODUCTION AND HISTORICAL PERSPECTIVE

The study of phosphate has led to a deep understanding of the chemistry that makes life on Earth possible. The use of reversible adsorption to solid support (RASS) allowed native DNA constructs to be manipulated as if they were small organic compounds Combining this technology with the exquisite chemoselectivity and high reactivity of Ψ toward O-nucleophiles enabled the direct synthetic elaboration of native DNA by RASS (SENDR, Figure 5B).[84] DNA hybridization probes underpin much of modern biochemical, diagnostic, and genomic techniques; ubiquitous, they are resource- and time-intensive to produce by total chemical synthesis when compared to biochemical processes.[85] Numerous attempts to react the free alcohol residues of DNA (3′ or 5′). Notes The authors declare the following competing financial interest(s): Three of the authors are co-founders of Elsie Biotechnologies, a company that is in the process of licensing some of the technology patented in this outlook

■ ACKNOWLEDGMENTS

■ REFERENCES

The reaction between carbodi-imides and acid esters of phosphoric